Int J Endocrinol Metab. 2011;9(4):369-372. DOI: 10.5812/Kowsar.1726913X.

3386

International Journal of

Endocrinology
KOWSAR
Metabolism
Journal home page: www.EndoMetabol.com

Tako-Tsubo Cardiomyopathy and Thyroid Dysfunction

Filippo M. Sarullo 1*, Antonino Di Franco 2, Antonio Di Monaco 2, Serena Magro 1, Roberto
Nerla 2, Ylenia Salerno 1, Giorgio Mandala 1, Gaetano A. Lanza 2
1 Cardiac Rehabilitation Unit, Buccheri La Ferla Fatebenefratelli Hospital, Palermo, Italy
2 Division of Cardiology, Catholic University of Sacred Heart, Rome , Italy

A R T IC LE I NFO A B S TRAC T

Article type: First described in a Japanese population in 1991, the Tako-Tsubo disease has recently been in-
Mini Review Article cluded among the primary acquired cardiomyopathies in the American Heart Associations
disease classifications. Tako-Tsubo cardiomyopathy (TTC) is a reversible, often misdiagnosed
Article history: condition, as it can easily mimic acute coronary syndrome. It has indeed been estimated that
Received: 04 Jun 2011 TTC can represent 1 to 2% of patients who present with suspected acute coronary syndrome.
Revised: 07 Aug 2011 The disease is especially common in women. In its typical presentation, the identifying
Accepted: 20 Aug 2011 characteristic of TTC is the systolic bulging of the hearts apex with preserved contraction
of basal myocardial segments. The acute left ventricular dysfunction, however, it is usually
Keywords: reversible, with contractile function usually recovering in a few weeks. The etiology of TTC is
Tako-Tsubo Cardiomyopathy not completely clear. Many theories have been proposed, taking into account the role of hor-
Thyroid Dysfunction mone disturbances, acute toxic effects of catecholamines on cardiomyocytes, diffuse micro-
Ventricular Function vascular spasms, multivessel epicardial spasms, and acute myocarditis. Several researchers
have suggested that TTC may occur as a rare complication of dysthyroidism. In particular, an
acute hyperthyroid state has been proposed to be capable of triggering TTC, independently
of its causes. Indeed, several cases of TTC associated with Graves disease, Hashimoto thy-
roiditis, or excess levothyroxine therapy have been reported in the medical literature. The
mechanism by which dysthyroidism can trigger TTC, however, remains poorly understood.
In this review we investigated the role of thyroid dysfunction as a possible trigger for TTC.
Copyright c 2011 Kowsar M. P. Co. All rights reserved.

Implication for health policy/practice/research/medical education:

This work provides important information about the correlation between Tako-Tsubo Cardiomyopathy (TTC) and Thyroid dysfunction
(TD). The article gives evidence to how doctors may have to refer to when confronted with a patients with such condiction as thyroid
dysfunction and TTC, and the diverse methods that can be used to treat these conditions (TTC with TD).

Please cite this paper as:

Sarullo FM, Di Franco A, Di Monaco A, Magro S, Nerla R, Salerno Y, et al. Tako-Tsubo Cardiomyopathy and Thyroid Dysfunction. Int J
Endocrinol Metab. 2011;9(4):369-72. DOI: 10.5812/Kowsar.1726913X.3386

1. Tako-Tsubo Disease of Tako-Tsubo cardiomyopathy (TTC; also variably known

First described in the Japanese population in 1991 (1),
Tako-Tsubo disease has recently been included among
the primary acquired cardiomyopathies in the American
Heart Associations disease classifications (2).
In its typical presentation, the identifying characteristic
* Corresponding author: Filippo Maria Sarullo, Cardiac Rehabilitation
Unit , Buccheri La Ferla Fatebenefratelli Hospital, Via Salvatore Puglisi
n.15, 90143 Palermo, Italy. Tel: +39-091479263, Fax: +39-091342336, E-mail:
fsarullo@neomedia.it
DOI: 10.5812/Kowsar.1726913X.3386
Copyright c 2011 Kowsar M.P.Co. All rights reserved.
as apical ballooning syndrome, stress cardiomyopathy, bro-
ken heart syndrome, and ampulla cardiomyopathy) is the
systolic bulging of the hearts apex with a preserved con-
traction of basal myocardial segments, so that, in systole,
the left ventricle forms a shape similar to a tako-tsubo, the
pot used by Japanese fishermen to catch octopus (1). TTC
is a reversible, often misdiagnosed condition, as it can eas-
ily mimic acute coronary syndrome. It has been estimated
that TTC can represent 1 to 2% of patients who present with
suspected acute coronary syndrome (3). The condition is es-
pecially prevalent in women, and postmenopausal women
have been reported to make up over 90% of the cases in
most study samples (4-6). The most common symptom is
370 Sarullo FM et al.
chest pain, variably accompanied by diaphoresis, dyspnea,
palpitations, nausea, or syncope. In some patients the clini-
cal presentation can be dramatic, including acute heart fail-
ure or cardiogenic shock, due to the severe impairment of
left ventricular function. The acute left ventricular dysfunc-
tion, however, is usually reversible, with contractile func-
tion usually recovering in a few weeks (5, 6). The condition
is associated with a preceding stressful event in about two-
thirds of cases. Both emotional (e.g., death of a family mem-
ber, financial disaster, severe argument) and physical (e.g.,
sepsis, cerebrovascular accidents, cocaine use, severe pain,
trauma, surgical interventions) stressors can act as triggers,
although TTC can occasionally occur in the absence of any
precipitating event (7, 8).
The etiology of TTC is not completely clear. Many theories
have been proposed, taking into account the role of hor-
mone disturbances, acute toxic effects of catecholamines
on cardiomyocytes, diffuse microvascular spasms, multi-
vessel epicardial spasms, and acute myocarditis. The fre-
quent association with stressful events suggests that an
acute activation of the adrenergic system plays a crucial
role in the pathogenesis of TTC. Notably, this is also support-
ed by evidence that the peculiar contractile impairment of
the middistal and apical segments of the left ventricle in
TTC patients seems to parallel the regional density of car-
diac adrenergic receptors (ARs). For instance, in a study
with canine subjects, Mori et al. (9) found that -ARs present
a higher expression in the apical region of the heart, with
a progressive decrease from apex to base. Accordingly, the
apical and distal regions of the heart will be more subject to
the negative effects of high catecholamine levels or sympa-
thetic outflow, compared to the midbasal segments. More-
over, findings from Lyon et al. (10) suggest that the differ-
ences in ARs throughout the heart might mainly concern
2-ARs, which, when stimulated by high concentrations of
circulating epinephrine (as achieved during strong stress
stimuli), can result in a paradoxical negative inotropic ef-
fect due to a switch in intracellular signals in the cardiomy-
ocytes from the Gs to the Gi protein. This intriguing hypoth-
esis, however, needs to be confirmed in further studies.
Acute and exaggerated sympathetic activation (11) can
result in cardiac dysfunction through a direct toxic ef-
fect on cardiomyocytes (i.e., adrenergic cardiomyopathy),
similar to that observed in other hyperadrenergic states,
such as pheochromocytoma (12) and subarachnoid hem-
orrhage (13). Accordingly, histologic abnormalities com-
patible with adrenergic cardiomyopathy, mainly consist-
ing of a focal necrosis with hypercontrated myocardial
fibers, have been reported in some patients with TTC (14).
Nonetheless, elevated levels of catecholamines can also
trigger TTC by inducing severe coronary artery constric-
tion, either in the epicardial vessels (15) or in the coro-
nary microcirculation (16). A severe, transient coronary
microvascular constriction has been hypothesized by
several authors (17-19), and the evidence suggests that
coronary flow reserve is impaired in the acute phase of
TTC but improves at short-term follow-up along with left
Int J Endocrinol Metab. 2011;9(4):369-372
Tako-Tsubo disease and dysthyroidism
ventricular function (20). At present, however, definitive
evidence of a major pathogenic role for coronary micro-
circulatory abnormalities in TTC is lacking because it is
possible that the impairment in microvascular function
is just an epiphenomenon of the disease rather than a
primary cause of the disease.
2. Thyroid and Tako-Tsubo Cardiomyopa-
thy
Several authors have suggested that TTC may occur
as a rare complication of dysthyroidism. In particular,
an acute hyperthyroid state has been proposed to be
capable of triggering TTC, independently of its causes.
Indeed, several cases of TTC associated with Graves dis-
ease (21-24), Hashimoto thyroiditis (25), or excess levothy-
roxine therapy (26) have been reported in the medical
literature (Table 1). The mechanisms by which hyperthy-
roidism (HT) trigger TTC, however, remain poorly under-
stood (Figure 1).
A rapid increase of thyroid hormones might result in an
acute activation of the adrenergic system, which, as dis-
Table 1. Cases of TTC Associated with HT
Cases of TTC Associated With HT Pts with TTC Mean Age, y
Miyazaki S et al. (21) 1 79
Bilan A et al. (22) 1 59
Rossor AM et al. (23) 1 61
Sarullo FM et al. (24) 1 55
Sakaki T et al. (25) 1 74
Gowda RM et al. (26) 1 69
cussed above, plays a major role in the pathogenesis of TTC
and might therefore be the effector of HT-triggered TTC.
Nevertheless, there is conflicting evidence from the medi-
cal literature regarding the interrelationship between the
thyroid and the adrenergic axis. Some studies have indeed
shown that, in HT plasma, catecholamine levels are usually
normal or less than normal (27). Other studies, however,
have suggested that thyroid hormones can exaggerate the
response to normal levels of catecholamines (28). Accord-
ingly, many authors have shown that variations in thyroid
hormone levels can alter the transcription of adrenergic
receptors, ultimately favoring the inotropic and chrono-
tropic stimulation of the heart (29). Thyroid hormones, on
the other hand, exert direct negative effects on the cardio-
vascular system that might be responsible for TTC. These
hormones are indeed known to alter heart rate, cardiac
output, and systemic vascular resistance. Furthermore, in
addition to increasing peripheral oxygen consumption
and substrate requirements, resulting in a secondary in-
crease in cardiac contractility, triiodothyronine, the active
form of thyroid hormones, can directly increase cardiac
inotropism (30, 31). After entering the myocardial cell by
means of specific transport proteins in the cell membrane,
triiodothyronine acts at the nuclear level by leading to tran-
Tako-Tsubo disease and dysthyroidism Sarullo FM et al. 371

DYSTHYROIDISM
(GRAVES DISEASE, HASHIM OTO THYROIDITIS, EXOESS OF LEVOTHYROXINE THERAPY)

INCREASE OF
THYROID
HORMONES

EXAGGERATED RESPONSE THYROTOXI C

CARDIOMYOPATHY
TO CATECHOLAMINES ?
?

DIRECT TOXIC EFFETC REDUD VENTRICULAR

ON MUITIVESSEL EPICARDIAL MICRO VASCULAR CONTRACTILITY AND DIASTOLIC
CARDIOMYOCYTES SPASM SPASM DYSFUNCTION

MID-DISTAL AND
APICAL CONTRACTILE
IMPAIRMENT

Figure 1. Proposed Mechanisms of Association Between Thyroid Dysfunction and Tako-Tsubo Cardiomyopathy (See Text)

scriptional activation of both the structural and regulatory
cardiac proteins, such as 1-adrenergic receptors (ARs),
-myosin heavy chain, Na+/K+ ATPase, voltage-gated potas-
sium channels, sarcoplasmic reticulum Ca++-ATPase, and
phospholamban, which are all involved in the regulation of
both systolic and diastolic function (32).
An excess of thyroid hormones, however, has been shown
to possibly result in dramatic impairment of left ventricular
function (33). The underlying pathophysiology of this thyro-
toxic cardiomyopathy remains unclear. In many cases it has
been attributed to a tachyarrhythmia-related depression of
the heart (tachyarrhythmia-mediated cardiomyopathy) lead-
ing to an increased level of cytosolic calcium during diastole
with reduced ventricular contractility and diastolic dysfunc-
tion (34). In a small subset of patients with persistent sinus
tachycardia or atrial fibrillation, low-output heart failure (thy-
rotoxic cardiomyopathy) can develop, although this is revers-
ible when a euthyroid state is reestablished (25, 31, 35, 36).
Still, TTC in HT patients might be triggered by multives-
sel epicardial artery spasms, which early studies suggested
to play a pathogenic role in some patients (1). Several stud-
ies have indeed suggested that vasospastic angina may be
induced in patients with both transient or persistent HT.
Featherstone and Stewart (37) also reported a patient with
hyperthyroid Graves disease who had vasospastic angina.
They demonstrated that, in a hypothyroid state, the patient
became free of angina after iodine 131 therapy, whereas the
patients angina returned in the hyperthyroid stage by in-
creasing levothyroxine sodium. Moliterno and colleagues
(38) reported a case in which the repeated occurrence of ep-
isodes of myocardial ischemia due to coronary spasms was
correlated with repeated transient elevations in thyroid
hormone levels. Vasospasm was also angiographically iden-
tified in a patient with occult HT by Wei et al. (39). Severe re-
versible ischemia due to excess thyroid administration has
also been reported (40). Finally, in a recent study, Cakir (41)
suggested that TTC might not be related to thyrotoxicosis
per se, but might be a complication of the autoimmunity
of thyroid disease, which is a new perspective of the puzzle.
Again, more studies are needed to confirm this idea.
In conclusion, the question of whether elevated thyroid
hormones levels can precipitate TTC is still debatable
and requires further research. Nevertheless, it is advis-
able that physicians look for a treatable underlying con-
dition in TTC patients because this requires a different
treatment plan. In this sense, a diagnosis of HT, although
rare, should be considered.
Acknowledgments
We thank Edna Sabina Salguero for assisting with the
English translation.

Int J Endocrinol Metab. 2011;9(4):369-372

372 Sarullo FM et al. Tako-Tsubo disease and dysthyroidism

Financial Disclosure 18. Elesber A, Lerman A, Bybee KA, Murphy JG, Barsness G, Singh M,
et al. Myocardial perfusion in apical ballooning syndrome cor-
None declared. relate of myocardial injury. Am Heart J. 2006;152(3):469 e9-13.
19. Fazio G, Sarullo FM, Novo G, Evola S, Lunetta M, Barbaro G, et al.
Tako-tsubo cardiomyopathy and microcirculation. J Clin Monit
Funding/Support Comput. 2010;24(2):101-5.
20. Galiuto L, De Caterina AR, Porfidia A, Paraggio L, Barchetta S, Lo-
None declared.
corotondo G, et al. Reversible coronary microvascular dysfunc-
tion: a common pathogenetic mechanism in Apical Ballooning
Refetrences or Tako-Tsubo Syndrome. Eur Heart J. 2010;31(11):1319-27.
21. Bilan A, Ignatowicz A, Mosiewicz J, Wysokinski A. Dyspnea as a
1. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. [Myocardial
dominant clinical manifestation in a patient with takotsubo
stunning due to simultaneous multivessel coronary spasms: a
cardiomyopathy treated for chronic obstructive pulmonary dis-
review of 5 cases]. J Cardiol. 1991;21(2):203-14.
ease and hyperthyroidism. Pol Arch Med Wewn. 2009;119(4):265-
2. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett
8.
D, et al. Contemporary Definitions and Classification of the Car-
22. Miyazaki S, Kamiishi T, Hosokawa N, Komura M, Konagai H, Sagai
diomyopathies. Circulation. 2006;113(14):1807-16.
H, et al. Reversible left ventricular dysfunction takotsubo car-
3. Kawai S, Suzuki H, Yamaguchi H, Tanaka K, Sawada H, Aizawa T,
diomyopathy associated with hyperthyroidism. Jpn Heart J.
et al. Ampulla cardiomyopathy (Takotusbo cardiomyopathy)-
2004;45(5):889-94.
-reversible left ventricular dysfunction: with ST segment eleva-
23. Rossor AM, Pearce SH, Adams PC. Left ventricular apical bal-
tion. Jpn Circ J. 2000;64(2):156-9.
looning (takotsubo cardiomyopathy) in thyrotoxicosis. Thyroid.
4. Desmet WJ, Adriaenssens BF, Dens JA. Apical ballooning of the left
2007;17(2):181-2.
ventricle: first series in white patients. Heart. 2003;89(9):1027-31.
24. Sarullo FM, Americo L, Accardo S, Cicero S, Schicchi R, Schiro M,
5. Sharkey SW, Lesser JR, Zenovich AG, Maron MS, Lindberg J,
et al. Tako-tsubo cardiomyopathy observed in a patient with
Longe TF, et al. Acute and Reversible Cardiomyopathy Pro-
sepsis and transient hyperthyroidism. Monaldi Arch Chest Dis.
voked by Stress in Women From the United States. Circulation.
2009;72(1):33-6.
2005;111(4):472-9.
25. Sakaki T, Fujioka Y, Akagami T, Masai M, Shimizu H, Sakoda T,
6. Tsuchihashi K, Ueshima K, Uchida T, Oh-mura N, Kimura K, Owa
et al. Cardiac wall motion abnormalities observed in a patient
M, et al. Transient left ventricular apical ballooning without cor-
with transient hyperthyroidism. Jpn Heart J. 2004;45(6):1071-7.
onary artery stenosis: a novel heart syndrome mimicking acute
26. Gowda RM, Khan IA, Soodini G, Vasavada BC, Sacchi TJ. Acute myo-
myocardial infarction. Angina Pectoris-Myocardial Infarction
cardial infarction with normal coronary arteries associated with
Investigations in Japan. J Am Coll Cardiol. 2001;38(1):11-8.
iatrogenic hyperthyroidism. Int J Cardiol. 2003;90(2-3):327-9.
7. Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E.
27. Polikar R, Burger AG, Scherrer U, Nicod P. The thyroid and the
Apical ballooning syndrome or takotsubo cardiomyopathy: a
heart. Circulation. 1993;87(5):1435-41.
systematic review. Eur Heart J. 2006;27(13):1523-9.
28. Gerald S L. Catecholamine sensitivity, thyroid hormone and the
8. Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG,
heart: A reevaluation. Am J Med. 1971;50(4):413-20.
Lesser JN, et al. Natural history and expansive clinical pro-
29. Walker JD, Crawford FA, Kato S, Spinale FG. The novel effects of
file of stress (tako-tsubo) cardiomyopathy. J Am Coll Cardiol.
3,5,3-triiodo-L-thyronine on myocyte contractile function and
2010;55(4):333-41.
beta-adrenergic responsiveness in dilated cardiomyopathy. J
9. Mori H, Ishikawa S, Kojima S, Hayashi J, Watanabe Y, Hoffman JI,
Thorac Cardiovasc Surg. 1994;108(4):672-9.
et al. Increased responsiveness of left ventricular apical myocar-
30. Dillmann WH. Biochemical basis of thyroid hormone action in
dium to adrenergic stimuli. Cardiovasc Res. 1993;27(2):192-8.
the heart. Am J Med. 1990;88(6):626-30.
10. Lyon AR, Rees PS, Prasad S, Poole-Wilson PA, Harding SE. Stress
31. Klein I. Thyroid hormone and the cardiovascular system. Am J
(Takotsubo) cardiomyopathy--a novel pathophysiological hy-
Med. 1990;88(6):631-7.
pothesis to explain catecholamine-induced acute myocardial
32. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular sys-
stunning. Nat Clin Pract Cardiovasc Med. 2008;5(1):22-9.
tem. N Engl J Med. 2001;344(7):501-9.
11. Lavi S, Nevo O, Thaler I, Rosenfeld R, Dayan L, Hirshoren N,
33. Pereira N, Parisi A, Dec GW, Choo J, Hajjar R, Gordon PC. Myocar-
et al. Effect of aging on the cardiovascular regulatory sys-
dial stunning in hyperthyroidism. Clin Cardiol. 2000;23(4):298-
tems in healthy women. Am J Physiol Regul Integr Comp Physiol.
300.
2007;292(2):R788-93.
34. Dahl P, Danzi S, Klein I. Thyrotoxic cardiac disease. Curr Heart Fail
12. Otsuka M, Kohno K, Itoh A. Periodic fluctuation of blood pres-
Rep. 2008;5(3):170-6.
sure and transient left ventricular apical ballooning in pheo-
35. Fadel BM, Ellahham S, Ringel MD, Lindsay J, Jr., Wartofsky
chromocytoma. Heart. 2006;92(12):1837.
L, Burman KD. Hyperthyroid heart disease. Clin Cardiol.
13. Naredi S, Lambert G, Eden E, Zall S, Runnerstam M, Rydenhag B, et
2000;23(6):402-8.
al. Increased sympathetic nervous activity in patients with non-
36. Kantharia BK, Richards HB, Battaglia J. Reversible dilated car-
traumatic subarachnoid hemorrhage. Stroke. 2000;31(4):901-6.
diomyopathy: an unusual case of thyrotoxicosis. Am Heart J.
14. Wittstein IS, Thiemann DR, Lima JAC, Baughman KL, Schulman
1995;129(5):1030-2.
SP, Gerstenblith G, et al. Neurohumoral Features of Myocar-
37. Featherstone HJ, Stewart DK. Angina in thyrotoxicosis. Thyroid-
dial Stunning Due to Sudden Emotional Stress. New Engl J Med.
related coronary artery spasm. Arch Intern Med. 1983;143(3):554-5.
2005;352(6):539-48.
38. Moliterno D, DeBold CR, Robertson RM. Case report: coronary
15. Adameova A, Abdellatif Y, Dhalla NS. Role of the excessive
vasospasm--relation to the hyperthyroid state. Am J Med Sci.
amounts of circulating catecholamines and glucocorti-
1992;304(1):38-42.
coids in stress-induced heart disease. Can J Physiol Pharmacol.
39. Wei JY, Genecin A, Greene HL, Achuff SC. Coronary spasm with
2009;87(7):493-514.
ventricular fibrillation during thyrotoxicosis: response to at-
16. Lanza GA, Crea F. Primary coronary microvascular dysfunction:
taining euthyroid state. Am J Cardiol. 1979;43(2):335-9.
clinical presentation, pathophysiology, and management. Circu-
40. Bergeron GA, Goldsmith R, Schiller NB. Myocardial infarction,
lation. 2010;121(21):2317-25.
severe reversible ischemia, and shock following excess thyroid
17. Bybee KA, Prasad A, Barsness GW, Lerman A, Jaffe AS, Murphy JG,
administration in a woman with normal coronary arteries. Arch
et al. Clinical characteristics and thrombolysis in myocardial in-
Intern Med. 1988;148(6):1450-3.
farction frame counts in women with transient left ventricular
41. Cakir M. Takotsubo cardiomyopathy in thyrotoxicosis. Int J Car-
apical ballooning syndrome. Am J Cardiol. 2004;94(3):343-6.
diol. 2010;145(3):499-500.

Int J Endocrinol Metab. 2011;9(4):369-372